Facilely Direct Construction, White-Light Emission, and Color-Adjustable Luminescence of LaF3 :Pr3+ @SiO2 Yolk-Shell Nanospheres with Moisture Resistance.

Poor water stability and single luminous color are the major drawbacks of the most phosphors reported. Therefore, it is important to realize multicolor luminescence in a phosphor with single host and single activator as well as moisture resistance. LaF3 :Pr3+ @SiO2 yolk-shell nanospheres are facilely obtained by a designing new technology of a simple and cost-effective electrospray ionization combined with a dicrucible fluorating technique without using protective gas. In addition, tunable photoluminescence, especially white-light emission, is successfully obtained in LaF3 :Pr3+ @SiO2 yolk-shell nanospheres by adjusting Pr3+ ion concentrations, and the luminescence mechanism of Pr3+ ion is advanced. Compared with the counterpart LaF3 :Pr3+ nanospheres, the water stability of LaF3 :Pr3+ @SiO2 yolk-shell nanospheres is improved by 15% after immersion in water for 72 h, and the fluorescence intensity can be maintained at 86% of the initial intensity. Furthermore, by treating the yolk-shell nanospheres with hydrofluoric acid, it is not only demonstrated that the shell-layer is SiO2 but also core-LaF3 :Pr3+ nanospheres are obtained. Particularly, only fluorination procedure among the halogenation can produce such special yolk-shell nanospheres, the formation mechanism of yolk-shell nanospheres is proposed detailedly based on the sound experiments and a corresponding new technology is built. These findings broaden practical applications of LaF3 :Pr3+ @SiO2 yolk-shell nanospheres.

Dual-Confinement Effect of Nanocages@Nanotubes Suppresses Polysulfide Shuttle Effect for High-Performance Lithium-Sulfur Batteries.

The shuttle effect of lithium polysulfides (LiPSs) severely hinders the development and commercialization of lithium-sulfur batteries, and the design of high-conductive carbon fiber-host material has become a key solution to suppress the shuttle effect. In this work, a unique Co/CoN-carbon nanocages@TiO2-carbon nanotubes structure (NC@TiO2-CNTs) is constructed using an electrospinning and nitriding process. Lithium-sulfur batteries using NC@TiO2-CNTs as cathode host materials exhibit high sulfur utilization (1527 mAh g-1 at 0.2 C) and can still maintain a discharge capacity of 663 mAh g-1 at a high current density of 5 C, and the capacity loss is only 0.056% per cycle during 500 cycles at 1 C. It is worth noting that even under extreme conditions (sulfur-loading = 90%, surface-loading = 5.0 mg cm-2 (S), and E/S = 6.63 µL mg-1), the lithium-sulfur batteries can still provide a reversible capacity of 4 mAh cm-2. Throughdensity functional theory calculations, it has been found that the Co/CoN heterostructures can adsorb and catalyze LiPSs conversion effectively. Simultaneously, the TiO2 can adsorb LiPSs and transfer Li+ selectively, achieving dual confinement for the shuttle effect of LiPSs (nanocages and nanotubes). The new findings provide a new performance enhancement strategy for the commercialization of lithium-sulfur batteries.

Pseudo-tricolor typed nanobelts and arrays simultaneously endowed with conductive anisotropy, magnetism and white fluorescence.

A novel [uniaxial needle]//[coaxial needle]//[uniaxial needle] parallel spinneret is first innovatively designed and manufactured by inserting a coaxial needle into the middle of a bi-axial parallel needle, and the corresponding spinning device is established. With the aid of the distinctive-structured spinneret and the spinning device, a novel and brand-new flexible one-dimensional nanobelt//coaxial nanobelt//nanobelt tri-strand parallel nanobelt, very much like a tricolor flag and named a pseudo-tricolor typed nanobelt, is successfully prepared by electrospinning technology for the first time. Microscopically, partition of four independent domains in the pseudo-tricolor typed nanobelt is realized, and such a partitioned structure can assemble various functions and helps reduce detrimental interactions among various functions to acquire excellent poly-functions of multifunctional nanomaterials. As a case study, {anthracene/Eu(2-thenoyltrifluoroacetone)3(triphenylphosphine oxide)2 [Eu(TTA)3(TPPO)2]/polymethylmethacrylate (PMMA)}//{[CoFe2O4/PMMA]@[polyaniline (PANI)/PMMA]}//{coumarin-6/PMMA} pseudo-tricolor typed nanobelts and arrays (abbreviated as [B + R]//[M@C]//[G] PNA) are designed and constructed via electrospinning. Each pseudo-tricolor typed nanobelt is composed of left and right sides of blue and red fluorescent [anthracene/Eu(TTA)3(TPPO)2/PMMA] nanobelts and green fluorescent [coumarin-6/PMMA] nanobelts, respectively, and the middle of the [CoFe2O4/PMMA]@[PANI/PMMA] coaxial nanobelt with magnetic-conductive bifunctionality using the CoFe2O4/PMMA nanobelt as the core and PANI/PMMA as the shell. Luminescence-magnetic-conductive polyfunctionalities are highly integrated but also mutually separated in the pseudo-tricolor typed nanobelt, and thus, both segregation and integration of the functions are actualized in the pseudo-tricolor typed nanobelt. A pseudo-tricolor typed nanobelt as the building unit ensures strong fluorescence and high conductive anisotropy of the array. Moreover, energy transfer between dyes is controlled by the special structure of the nanobelt and thus white light emission is realized by the combination of europium complexes with the dyes. The conductive anisotropy and magnetism of the array are tuned by changing the content of PANI and CoFe2O4, respectively. The formation mechanism of the pseudo-tricolor typed nanobelt is proposed, and new techniques for constructing nanobelts and arrays are established. This kind of pseudo-tricolor typed nanobelt with four functional subareas possesses important implications as a building unit to construct other polyfunctional nanostructures. More importantly, the design philosophy and the construction techniques for the novel pseudo-tricolor typed nanobelt and array afford some guidance for the development of other multifunctional materials.

Mild Condition for the Deoxygenation of α-Heteroaryl-Substituted Methanol Derivatives.

A mild condition via PPh3/I2/imidazole for the deoxygenation of substituted methanol derivatives has been identified. This metal-free process was found to proceed well on secondary or tertiary alcohols substituted with one or two heteroaryl groups, and it tolerates acid-sensitive heterocycles. This condition works for methanol derivatives substituted with 2-pyridyl, 4-pyridyl, or other heterocyclic groups, allowing the negative charge formed during the reaction to resonate to a nitrogen atom. Methanol derivatives substituted with 3-pyridyl or heterocyclic groups that do not allow the negative charge formed during the reaction to resonate to a nitrogen atom will not undergo deoxygenation under this condition.

Discovery of macrocyclic HDACs 1, 2, and 3 selective inhibitors for HIV latency reactivation.

A series of unique macrocyclic HDACs 1, 2, and 3 selective inhibitors were identified with good enzymatic activity and high selectivity over HDACs 6 and 8. These macrocyclic HDAC inhibitors used an ethyl ketone as the zinc-binding group. Compounds 25 and 26 stood out as leads due to their low double-digit nM EC50s in the 2C4 cell-based HIV latency reactivation assay. The PK profiles of these macrocyclic HDAC inhibitors still needed improvement.

Discovery of IDO1 inhibitors containing a decahydroquinoline, decahydro-1,6-naphthyridine, or octahydro-1H-pyrrolo[3,2-c]pyridine scaffold.

A series of IDO1 inhibitors containing a decahydroquinoline, decahydro-1,6-naphthyridine, or octahydro-1H-pyrrolo[3,2-c]pyridine scaffold were identified with good cellular and human whole blood activity against IDO1. These inhibitors contain multiple chiral centers and all diastereomers were separated. The absolute stereochemistry of each isomers were not determined. Compounds 15 and 27 stood out as leads due to their good cellular as well as human whole blood IDO1 inhibition activity, low unbound clearance, and reasonable mean residence time in rat cassette PK studies.

SAR towards indoline and 3-azaindoline classes of IDO1 inhibitors.

A novel series of IDO1 inhibitors have been identified with good IDO1 Hela cell and human whole blood activity. These inhibitors contain an indoline or a 3-azaindoline scaffold. Their structure-activity-relationship studies have been explored. Compounds 37 and 41 stood out as leads due to their good potency in IDO1 Hela assay, good IDO1 unbound hWB IC50s, reasonable unbound clearance, and good MRT in rat and dog PK studies.

Selective N7 Alkylation of 7-Azaindazoles.

A general and mild procedure for alkylation of 7-azaindazoles at the N7 position using alkyl halides in butanone is reported, which requires no additives such as acids or bases. The scope of the reaction regarding substituents on 7-azaindazoles and the alkyl electrophiles is presented.

Development of a selective HDAC inhibitor aimed at reactivating the HIV latent reservoir.

The synthesis and SAR development of a trisubstituted imidazole HDAC inhibitor is described. The compounds were synthesized with high diastereocontrol by leveraging Ellman sulfinyl imine chemistry. Structural elucidation provided insight into binding mode and supported design rational. Pharmacokinetic properties of lead compounds were determined.

Discovery of ethyl ketone-based HDACs 1, 2, and 3 selective inhibitors for HIV latency reactivation.

A novel series of ethyl ketone based HDACs 1, 2, and 3 selective inhibitors have been identified with good enzymatic and cellular activity and high selectivity over HDACs 6 and 8. These inhibitors contain a spirobicyclic group in the amide region. Compound 13 stands out as a lead due to its good potency, high selectivity, and reasonable rat and dog PK. Compounds 33 and 34 show good potency and rat PK profiles as well.

Potent, non-covalent reversible BTK inhibitors with 8-amino-imidazo[1,5-a]pyrazine core featuring 3-position bicyclic ring substitutes.

Bruton's tyrosine kinase (BTK) is a Tec family kinase with a well-defined role in the B cell receptor (BCR) pathway. It has become an attractive kinase target for selective B cell inhibition, and for the treatment of B cell related diseases. Many BTK inhibitors have been discovered for the treatment of cancer and rheumatoid arthritis, including a series of BTK inhibitors based on 8-amino-imidazo[1,5-a]pyrazine we recently reported. The X-ray crystal structures of BTK with inhibitors were also published, which provided great help for the SAR design. Here we report our SAR work introducing ring constraints for the 3-position piperidine amides on the BTK inhibitors based on 8-amino-imidazo[1,5-a]pyrazine. This modification improved the potency in BTK inhibitions, as well as the PK profile and the off-target selectivity. The dose-dependent efficacy of two BTK inhibitors was observed in the rat collagen induced arthritis (CIA) model.

Luminescence properties and energy transfer of Tb3+, Eu3+ co-doped YTaO4 phosphors obtained via sol-gel combustion process.

Tantalate is considered as a valuable and efficient luminescence host because of its intense absorption in the ultraviolet area and excellent chemical properties. In this work, a series of pure YTaO4:Eu3+ and/or Tb3+ crystals were prepared via a sol-gel combustion method. The morphology, structure, and optical properties of the samples were discussed in detail. The Eu3+, Tb3+ co-doped YTaO4 samples are consisted of small spherical particles of around 18 nm. The prepared YTaO4:Tb3+ and/or Eu3+ samples exhibit the characteristic wide excitation band around 210-300 nm, the characteristic narrow red emission of Eu3+ (5D0 → 7F2) transitions and green emission of the Tb3+ (5D4 → 7F5) transitions when excited by UV light. It is focused on the energy transfer processes from the YTaO4 to Tb3+ as well as Eu3+ ions and from Tb3+ to Eu3+ ions of YTaO4:Eu3+/Tb3+ phosphors. Color-tunable emissions are realized through adjusting the types of rare earth ion (Eu3+ and Tb3+) and relative doping concentrations excited by a single wavelength. That is to say, the obtained Tb3+ and Eu3+ co-doped YTaO4 phosphors have a promising prospect in lasers, white light diodes (WLED), fluorescent lamp, and field emission display devices, etc.

Discovery of novel pan-genotypic HCV NS5A inhibitors containing a novel tetracyclic core.

A series of novel tetracyclic core-containing HCV NS5A inhibitors has been discovered. Incorporation of tetrahydropyran-substituted amino acid moiety improved their potency and yielded HCV NS5A inhibitors with a minimum potency shift from the GT1a strain compared to other genotypes and mutants. Compounds 53 and 54 showed the best potency profile and had reasonable half-times in rat PK studies. However, further optimization of their oral bioavailability is still needed in order to advance them for further development. [BMCL ABSTRACT] ©2000 Elsevier Science Ltd. All rights reserved.

Utilizing modules of different functions to construct a Janus-type membrane and derivative 3D Janus-type tube displaying synchronous trifunction of conductive aeolotropism, magnetism and luminescence.

The microstructures and macrostructures play a crucial role in the properties and applications of multifunctional materials. Herein, microscopic partition and macroscopic partition are combined by devising and preparing different modules that can be elaborately devised to possess specific performances. A two-dimensional (2D) 3-module Janus-type membrane multifunctionalized by conductive aeolotropism, magnetism and luminescence (defined as 3M-CML Janus-type membrane) is constructed via electro-spinning. The modular structure of 3M-CML Janus-type membrane is obtained by devising and constructing three different modules, including luminescence module (denoted as L module), conductive aeolotropism-luminescence module (marked as C-L module) and magnetism-luminescence module (named as M-L module). The results prove that almost no mutual detrimental influences exist among different modules owing to the macroscopic modular structure and Janus-type structure, which effectively avoids the negative interactions among different materials. Tb(BA)3phen/PVP nanofiber, [PMMA/Eu(BA)3phen]//[PMMA/PANI] Janus-type nanoribbon and [PMMA/Tb(BA)3phen]//[PMMA/Fe3O4] Janus-type nanoribbon are, respectively, selected as building units of the three modules, which further prevents the negative interactions among different materials and improves the versatility of 3M-CML Janus-type membrane. The luminescence, adjustable conductive aeolotropism and variable magnetism of 3M-CML Janus-type membrane are systematically discussed. Meanwhile, novel flexible four types of brand-new three-dimensional (3D) Janus-type tubes are obtained by rolling modularly devised 2D 3M-CML Janus-type membrane with different rolling schemes. As derivatives of the 2D 3M-CML Janus-type membranes, macroscopic 3D Janus-types tubes exhibit similar performances to 2D 3M-CML Janus-type membranes. The 2D Janus-type membrane and 3D Janus-type tube will have momentous applications in flexible electronics and nanodevices in the future.

In Vitro Antiviral Profile of Ruzasvir, a Potent and Pangenotype Inhibitor of Hepatitis C Virus NS5A.

Inhibition of NS5A has emerged as an attractive strategy to intervene in hepatitis C virus (HCV) replication. Ruzasvir (formerly MK-8408) was developed as a novel NS5A inhibitor to improve upon the potency and barrier to resistance of early compounds. Ruzasvir inhibited HCV RNA replication with 50% effective concentrations (EC50s) of 1 to 4 pM in Huh7 or Huh7.5 cells bearing replicons for HCV genotype 1 (GT1) to GT7. The antiviral activity was modestly (10-fold) reduced in the presence of 40% normal human serum. The picomolar potency in replicon cells extended to sequences of clinical isolates available in public databases that were synthesized and tested as replicons. In GT1a, ruzasvir inhibited common NS5A resistance-associated substitutions (RASs), with the exception of M28G. De novo resistance selection studies identified pathways with certain amino acid substitutions at residues 28, 30, 31, and 93 across genotypes. Substitutions at position 93 were more common in GT1 to -4, while changes at position 31 emerged frequently in GT5 and -6. With the exception of GT4, the reintroduction of selected RASs conferred a ≥100-fold potency reduction in the antiviral activity of ruzasvir. Common RASs from other classes of direct-acting antiviral agents (DAAs) did not confer cross-resistance to ruzasvir. The interaction of ruzasvir with an NS3/4A protease inhibitor (grazoprevir) and an NS5B polymerase prodrug (uprifosbuvir) was additive to synergistic, with no evidence of antagonism or cytotoxicity. The antiviral profile of ruzasvir supported its further evaluation in human trials in combination with grazoprevir and uprifosbuvir.

MK-8325: A silyl proline-containing NS5A inhibitor with pan-genotype activity for treatment of HCV.

HCV NS5A inhibitors have shown impressive in vitro potency profiles in HCV replicon assays thus making them attractive components for inclusion in an all oral fixed dose combination regimen. Herein, we describe the discovery and characterization of silyl proline-containing HCV NS5A inhibitor MK-8325 with good pan-genotype activity and acceptable pharmacokinetic properties.

Controlled Morphology, Improved Photoluminescent Properties, and Application of an Efficient Non-rare Earth Deep Red-Emitting Phosphor.

Transition-metal tetravalent manganese ions (Mn4+) as luminescence center of red phosphors have drawn much attention owing to their broad-band absorption extended from UV to blue regions and narrow red-emissive band. In the present work, a series of Mn4+-doped BaGeF6 red phosphors were obtained via hydrothermal method. X-ray powder diffraction, energy-dispersive X-ray spectrometer, scanning electron microscope, and photoluminescence spectra were employed to determine the crystal structure, composition, morphology, and photoluminescence properties of all samples. The prepared BaGeF6:Mn4+ samples demonstrate two dominant broadband absorption at near-UV (∼366 nm) and blue regions (∼470 nm) and intense red emissions (∼635 nm) under 470 nm excitation. In addition, the morphology and the emission intensities were successfully controlled by adjusting doping concentrations, reaction times, reaction temperatures, barium sources, and surfactants. Concentration quenching and thermal quenching mechanisms were studied in detail. When the BaGeF6:Mn4+ red phosphor was introduced into the light-emitting diode, warm white light-emitting diodes (w-LEDs) were successfully fabricated, which have high color rendering index (Ra = 86.3) and low correlated color temperature (4766 K), indicating that the BaGeF6:Mn4+ red phosphor provides a good opportunity for application in w-LEDs.

Development of a prodrug of hydantoin based TACE inhibitor.

Our research on hydantoin based TNF-α converting enzyme (TACE) inhibitors led to fused bi-heteroaryl hydantoin series that demonstrate sub-nanomolar potency (Ki) as well as excellent activity in human whole blood (hWBA). However, lead compound 2 posed some formulation challenges which prevented it for further development. A prodrug approach was investigated to address this issue. The pivalate prodrug 3 can be formulated as stable neutral form and demonstrated improved DMPK properties when compared with parent compound.

Fused bi-heteroaryl substituted hydantoin compounds as TACE inhibitors.

We have identified a series of hydantoin-derived TNF-a converting enzyme (TACE) inhibitors containing a pendant fused bi-heteroaryl group, which demonstrate sub-nanomolar potency (Ki), excellent activity in human whole blood assay, and improved DMPK profiles over prior series.

Discovery of novel BTK inhibitors with carboxylic acids.

We report the design and synthesis of a series of novel Bruton's Tyrosine Kinase (BTK) inhibitors with a carboxylic acid moiety in the ribose pocket. This series of compounds has demonstrated much improved off-target selectivities including adenosine uptake (AdU) inhibition compared to the piperidine amide series. Optimization of the initial lead compound 4 based on BTK enzyme inhibition, and human peripheral blood mononuclear cell (hPBMC) and human whole blood (hWB) activity led to the discovery of compound 40, with potent BTK inhibition, reduced off target activities, as well as favorable pharmacokinetic profile in both rat and dog.